This application lists 6 specific aims intended to further define the anatomy, biochemistry and physiology of a peptide-containing neural projection arising from the first trigeminal division and protecting to cranial arteries. A multidisciplinary approach will explore these aims using (a) retrograde axonal transport studies and immunohistochemistry (IHC) to determine neural connectivity between perivascular sensory fibers surrounding cranial arteries, cell bodies in trigeminal ganglia and central endings in brain stem, (b) IHC and radioimmunoassay (RIA) (with and without neurosurgical lesions) to identify biochemically, putative transmitter substances in these fibers, (c) IHC plus electron microscopy to describe their ultrastructural characteristics, (d) 14C 2-deoxyglucose method to study the activation of trigeminovascular fibers (by intraluminal vasodistension via balloon-tipped catheter) on the metabolism of discrete brain regions. Animal models will be developed to study the effects of activating the trigeminovascular system on vascular pathophysiology such as perivascular inflammation; these will include models of induced injury such as by chemicals. The effects of neurotransmitter receptor blockers and lesioning the trigeminovascular system on the natural history of induced injuries will be examined. Preliminary evidence suggests that destruction of these nerve fibers significantly modifies the development of chemically-induced brain inflammation. By taking such an approach, we hope to explore possible roles for the trigeminovascular system in response to brain injury and its vasculature, and develop treatments which would be expected to block the development of these changes.